5-(phenylstryl)-3methylisoxazoles

ABSTRACT

Novel 5-( Alpha -phenylstyryl)-3-methylisoxazoles, processes for preparing the same and intermediates produced by said processes. The novel compounds of this invention are useful for treating hyperlipemic states in animals, including mammals.

iJnited States Patent [72] Inventor Daniel Lednlcer Portage, Mich.

211 Appl. No. 867,937

[22] Filed Oct. 20, 1969 [45] Patented Nov. 30, 1971 [73] Assignee TheUpjohn Company Kalamazoo, Mich.

[541 5-(PHENYLSTRYL)-3METHYLISOXAZOLES 11 Claims, No Drawings [52] US.Cl 260/240 D, 260/307 H, 424/272 [51] int. Cl C07d 85/22 [50] Field ofSearch 260/240 D [56] References Cited OTHER REFERENCES Boris et al..Arch. Intern. Pharmacodyn. l5l (3- 4). 475- 489 l964).

Primary Examiner-Henry R. Jilcs Assistan! ExaminerG. Thomas ToddAttorneys-John Kekich and Earl C. Spaeth ABSTRACT: NovelS-(a-phenylstyryl)-3-methylisoxazoles, processes for preparing the sameand intermediates produced by said processes. The novel compounds ofthis invention are useful for treating hyperlipemic states in animals,including mammals.

1. -(PHENYLSTRYL)-3-METHYLISOXAZOLES BRIEF SUMMARY OF THE INVENTION Thisinvention relates to novel S-(a-phenylstyryD-3- methylisoxazoles andprocesses for preparing the same. The novel compounds of this inventionhave the formula:

wherein R is selected from the group consistingof hydrogen, alkyl offrom one to three carbon atoms, inclusive, hydrdxy, alkoxy of from oneto three carbon atoms, inclusive, alkano'yloxy of from one to threecarbon atoms, inclusive, and the group 4 wherein R, is selected from thegroup consisting of hydrogen, alkyl-of from one to three carbon atoms,inclusive, alkoxy of from one to three carbon atoms, inclusive, andalkanoyloxy of from one to three carbon atoms, inclusive, R, is the sameas above, and X is halo, preferably chloro or bromo.

from one to three carbon atoms, inclusive, alkoxy of from one 3 w lhre'ebon at m inslusivstand balsa:

Examples of halo are 'fluoro, chloro and bromo. Examples of alkyl offrom one to three carbon atoms, inclusive, are methyl, ethyl, propyl andisomeric forms thereof. Examples of alkoxy of from one to three carbonatoms, inclusive, are methoxy, ethoxy, propoxy and isomeric formsthereof. Examples of alkanoyloity of from one to three carbon atoms,inclu-- sive, are formyloxy, acetoxy and propionyloxy. The term residueof a saturated heterocyclic amine of five to seven ring members,inclusive" is inclusive of pyrrolidino-, lower alkylpyrrolidino such as2-methylpyrrolidino-, 2,2-dimethylpyrrolidino-, 3-methylpyrrolidino andthe like; piperazino, lower alkylpiperazino such as Z-methylpiperazine,4-methylpiperazino-, 2,4-dimethylpiperazino, and the like; piperidino,lower alkylpiperidino such as Z-methyipiperidino, 3-methylpiperidino,4,4-dimethylpiperidino, and the like; morpholino, hexamethyleniri ino,homopiperazjno and the like.

The term novel compounds of thisinvention" as used throughout thespecification embraces the compounds represented by formula I above,including the acid addition salts and quaternary ammonium salts of saidcompounds that contain tertiary amino groups, and the alkali metal anda! kaline earth metal salts-of the compoundsof-formula I wherein P'F FP-3hXQFBZiX- 7.. v The processes for making the novel compounds areillustrated by the following equations:

Hao I R1 i (@i Q5 3 rg Y X- IIa HI butyl/ thlur1 1 BIC I K34; 0- 0-11,

wherein R, is selected from the group consisting of hydrogen and alkylof from one to two carbon atoms, inclusive, and R is the same as above.

wherein X, R ,-Rg, R and n are the same as above.

wherein X and R, are the same as above, and R is selected from the groupconsisting of hydrogen, alkyl of from one to three carbon atoms,inclusive, alkoxy of from one to three carbon atoms, inclusive, and

51. O(CnH1n) H\ as defined above.

DETAILED DESCRIPTION Process A, which involves the Wittig reaction, isconducted by reacting a phenyl 3-methyl-5-isoxazolyl ketone llawith theylide prepared from the appropriately substitutedtriphenylbenzylphosphonium halide Ill and butyl lithium in the presenceof a solvent such as tetrahydrofuran. Other solvents that can be usedinclude diethyl ether, benzene and dioxane. The molar ratio of 11a to ll 1 can vary from 1:1 to 1:2 and the reaction temperature from -80 C.The product can be recovered from the reaction mixture bycrystallization, evaporation, chromatography and combinations thereof.

The starting ketone I la can be prepared by methods illustrated by thefollowing flow scheme:

Step1 if -oo,H

H CH; 0 a R.

Ste 2 r a? \O v1 0 A He Step Sl Step] CH3 CH3 Step4 N/ -c0Nn, N/\ -cN ov" 0 VIII Step 1 involves convening 3-methylisoxazole-S-carboxylic acidV to its acid chloride VI. The ketone Ila can be prepared from VI byeither of two methods. In the first method, VI is converted to theketone 11a by the well known Friedel-Crafts acylation step 2. In thesecond method, VI is converted to the corresponding amide VII step 3;the amide is converted to the corresponding nitrile VIII step 4, which,in turn, is converted to the ketone 11a step 5 by reacting it with theappropriate Grignard reagent. The starting material V is readilyavailable and the procedures utilized in the steps illustrated in flowscheme E are all well known in the art.

In Process 8, a S-[a-(p-alkanoyloxyphenyl)styryl]-3- methyl-isoxazole lbis saponified under mild basic conditions to yield the correspondingS-[a-(p-hydroxyphenyl)styryll-B- methyl-isoxazole 10. For example, 1bcan be heated at reflux in the presence of a solution of sodiumhydroxide in methanol.

In Process C, 1c is etherified by treating it with a(tertiaryamino)alkyl halide IV in the presence of a base such as sodiumhydride, sodium amide, sodium hydroxide, sodium methoxide and the like.The etherification is conducted advantageously in the presence of aninert organic solvent such as benzene, tetrahydrofuran, dioxane anddimethylformamide, or mixtures thereof.

In Process D, a phenyl 3-methyl-5-isoxazolyl ketone lb is reacted withthe Grignard reagent prepared from a benzyl halide and magnesium. Thereaction is conducted in the presence of an inert solvent such as eitheror tetrahydrofuran at a temperature of 040 C. The resulting crudealcohol is dehydrated by heating in an inert solvent such as benzene,toluene or xylene in the presence of a strong acid such asptoluenesulfonic acid, with azeotropic removal of the liberated water.

In all of the above processes, the products can be recovered -from thereaction mixtures by conventional procedures such as crystallization,evaporation, chromatography and combinations thereof.

The acid addition salts of the invention comprise the salts of thecompounds of formula I, wherein R is (tertiary-amino)-alkoxy, withpharmacologically acceptable acids such as sulfuric, hydrochloric,nitric, phosphoric, lactic, benzoic methane-sulfonic, -toluenesulfonic,salicylic, acetic, propionic, maleic, malic, tartaric, citric,cyclohexanesulfamic, succinic, nicotinic, ascorbic acids, and the like.

The quaternary ammonium salts of the invention are the salts obtained byreacting the tertiary-amino compounds of formula 1 with quatematingagents, for example alkyl halides, dialkyl sulfates, aralkyl halides,alkyl-arylsulfonates, and the like. The tenn alkyl" means alkyl of fromone to four carbon atoms, inclusive. The term alkenyl" means alkenyl offrom three to eight carbon atoms, inclusive, such as allyl, 2-butenyl,2-pentenyl, 2-hexenyl, Z-heptenyl, Z-octenyl, and isomeric formsthereof. The term aralkyl" means an aralkyl group containing from sevento l3 carbon atoms, inclusive, such as benzyl, phenethyl, Z-phenylpropl,benzhydryl and the like. The term alkyl arylsulfonates" means the estersformed from alkanols and arysulfonic, and like acids. Examples ofquaternary salts of the compounds of the invention are the methobromide,methiodide, ethobromide, propyl chloride, butyl bromide, methylmethosulfate, ethyl cthosulfate, allyl chloride, allyl bromide, benzylbromide, benzhydryl chloride, methyl p-toluenesulfonate, ethylp-toluenesulfonate and the like.

The compounds of the invention exhibit pharmacological activity inanimals, including mammals. For example, they are useful in thetreatment of hyperlipemic states in rats. The results of test whereinsome of the novel compounds of this invention were utilized to treathyperlipemic states in rats are set forth in the following table. Theresults are expressed in terms of minimum effective dosages (mg/kg.)required to significantly lower lipids with respect to controls. Thistype of assay is described by Garattini et al, Drugs Affective LipidMetabolism," page I44, Elsevier, Ams.

TABLE 1 Inc R ,f \O H Efi'cctlvo doso, No. R It; rnqJkg.

1 p OCH; II 1 Mixture otlsoruers. .2"... p-OCH; ll 25 Isomor A. 8"...19-0011 p-Clh 26 lsomer A. 4... p-OOH; p-CH; l lsomer ll.

p-OCH; Ell-Cl l 6. p-OCOOH; l 7--. p- H H 25 8 p-OCHzCHzN H lHydrochloride.

Some of the novel compounds of this invention also exhibit antifertilityactivity. For example, -[a-(p-methoxy phenyl)-m-methoxystyryll-3-methylisoxazole,5-[a-(p-hydroxy-phenyl)styryll-3-methylisoxazole, and 3-methy1-5-[a-]8p-[2-( lpyrrolidinyl)ethoxyl]phenyl]styryl]isoxazole hydrochlorideexhibit oral antifertility activity in rats when administered in dosagesof50 mg./kg.

For purposes of administration to birds and to mammals, includinganimals of economic value such as horses, cattle, sheep, pigs, mice,rats, rabbits and the like, the novel compounds of the invention can becombined with solid or liquid pharmaceutical carriers and formulated inthe form of tablets, powder packets, capsules and the like solid dosageforms, using starch and like excipients, or dissolved in suitablesolvents or vehicles for oral or parenteral administration.

Also, for mammals and birds food premixes, with starch, oatmeal, driedfishmeat, fishmeal, flour and the like can be prepared.

The novel compounds of this invention having the formula 1 wherein R is(tertiary-amino)alkoxy also form thiocyanic acid addition salts which,when condensed with formaldehyde, form resinous materials useful aspickling inhibitors according to US. Pat. No. 2,425,320 and U.S. Pat.No. 2,606,155. The fluosilicic acid addition salts are useful asmothproofing agents according to U.S. Pat. Nos. 1,915,334 and 2,075,359.

The following examples are set forth to illustrate my invention and toenable persons skilled in the art to better understand and practice theinvention and are not intended to limit the same.

PREPARATION A p-METHQXYPHENYL 3- METHYL-Sl-JSOXAZOLYL KETONE Method 1(Friedel Crafts) To a stirred, ice-cold solution of 20 ml. of anisole in300ml. of carbon disulfide is added 5.0 g. of aluminum chloride. To thismixture a solution of acid chloride from 5.0 g. of 3-methylisoxazole-S-carboxylic acid in 60 ml. of carbon disultide is addedover a period of 1 hour. The resulting mixture is allowed to stand atroom temperature for 17 hours and then poured into a mixture containing250 ml. of ice and 250 ml. of concentrated hydrochloric acid. Theaqueous layer is separated and washed twice with ether. The combinedorganic layers are evaporated with a stream of nitrogen. The residue isdissolved in ether. The resulting solution is washed successively withaqueous sodium bicarbonate solution, water and saturated aqueous sodiumchloride solution and then taken to dryness. The residue ischromatographed on 2 liters of magnesium silicate (Florisil) with 2.5percent acetone 97.5 percent Skellysolve B hexanes (by volume); 400 ml.fractions are collected. The fractions containing crystalline materialare combined. The crystalline material is recrystallized from aqueousmethanol to give 1.58 g. of p-methoxyphenyl 3-methyl-5-isoxazolylketone, melting point 70-73 C.

Method 2 (Grignard) A solution of 2.16 g. of3-methylisoxazole-5-carbonitrile in 30 ml. of tetrahydrofuran is addedto the ice-cooled Grignard reagent prepared from 4.10 g. ofpbromoanisole and 0.54 g. of magnesium in 50 m1. of tetrahydrofuran.Following 18 hours standing at room temperature, 50 ml. of saturatedaqueous ammonium chloride solution is added and the organic and aqueouslayers are separated. The organic layer is washed, in

turn, with water and saturated aqueous sodium chloride solution and thentaken to dryness. The residue is mixed with ml. of methanol and 25 ml.of 2.5N hydrochloric acid. Following 3 hours stirring at roomtemperature, most of the solvent is removed under reduced pressure. Themixture is extracted with ether and the extract is dried and evaporatedto dryness. The residue is chromatographed on 250 ml. of Florisil with7.5 percent acetone 92.5 percent Skellysolve B hexanes (by volume); 250ml. fractions are collected. The crystalline fractions are combined andrecrystallized from acetone Skellysolve B hexanes to give 0.97 g. ofp-methoxyphenyl 3- methyl-S-isoxazolyl ketone, melting point 63-67 C.

Anal.

Calcd. for C,,H,,N0 N, 6.45.

PREPARATION B p-HYDROXYPHENYL 3- METHYLS-ISOXAZOLYL KETONE A solution of2.0 g. of p-methoxyphenyl 3-methyl-5-isox azolyl ketone (Preparation A)in 10 ml. of acetic acid and 10 -ml. of 48 percent hydrobromic acid isheated at reflux for 4 hours. The resulting mixture is diluted withwater and extracted with ether. The organic layer is washed, in turn,with water and aqueous sodium bicarbonate solution, and then extractedwith four 24 ml. portions of 10 percent aqueous sodium hydroxidesolution. Acidification of the extract with dydrochloric acid yields afine precipitate which is extracted from the mixture with methylenechloride-ether. This last extract is taken to dryness and the residue isrecrystallized twice from acetone Skelly solve B hexanes to give [.10 g.of phydroxyphenyl 3-methyl-5-isoxazolyl ketone, melting point l80.5-l82C.

Anal.

Calcd. for C H,NO,: C, 65.02; H, 4.46.

Found: C, 64.67; H, 4.19.

Using the procedure of Preparation B, but replacing pmethoxyphenyl3-methyl-5-isoxazolyl ketone by o-methoxyphenyl 3-methyl-5-isoxazolylketone and m-methoxyphenyl 3-methyl-5-isoxazolyl ketone is productive ofo-hydroxyphenyl 3-methyl-5-isoxazolyl ketone and m-hydroxyphenyl 3-methyl-5 -isoxazolyl ketone, respectively.

PREPARATION C p-ACETOXYPHENYL 3-METHYL- 5-lSOXAZOLYL KETONE A mixture of4.34 g. of p-hydroxyphenyl 3-methyl-5-isoxazolyl ketone (Preparation B)and 40 m1. of acetic anhydride is heated at reflux for 4 hours. Theexcess acetic anhydride is removed under high vacuum. The residue isrecrystallized from ethyl acetate to give 5.0 g. of p-acetoxyphenyl3-methyl- 5-isoxazolyl ketone, melting point 1 l9-l22 C.

Anal. Calcd. for C H Nm: C, 63.67; H, 4.52.

Found: C, 63.61; H, 4.62.

Using the procedure of Preparation C, but replacing phydroxyphenyl3-methyl-5-isoxazolyl ketone by o-hydroxyphenyl 3-methyl-5-isoxazolylketone and m-hydroxyphenyl S-methyl-S-isoxazolyl ketone is productive ofo-acetoxyphenyl 3-methyl-5-isoxazolyl ketone and m-acetoxyphenyl3-methyl- S-isoxazolyl ketone, respectively.

Using the procedure of Preparation C, but replacing acetic anhydridewith propionic anhydride and acetic formic anhydride is productive ofp-propionyloxyphenyl 3-methyl-5- isoxazolyl ketone and p-formyloxyphenyl3-methyl-5-isoxazolyl ketone. respectively.

EXAMPLE 1 S-[a-(p-METHOXYPHENYL)STYRYLJ-S-METHYLISOX- AZOLE (MIXTURE OFISOMERS) A solution of 0.97 g. of p-methoxyphenyl 3-methyl-5-isoxazolylketone (Preparation A) in 50 ml. of ether is added to the Grignardreagent prepared from 1.50 g. of benzyl chloride and l g. of magnesiumin 25 ml. of ether. Following 16 hours standing at room temperature, 50ml. of saturated aqueous ammonium chloride solution is added and theorganic and aqueous layers are separated. The organic layer is washed,in turn, with water and saturated aqueous sodium chloride solution andthen taken to dryness. The residue is chromatographed on 200 ml. ofFlorisil with 5 percent acetone 95 percent Skellysolve B hexanes (byvolume); 200 ml. fractions are collected. The oily fractions arecombined to yield 1.05 g. of crude product. A mixture of this oil and100 mg. of ptoluenesulfonic acid in 100 ml. of benzene is heated under aDean-Stark trap overnight. The resulting solution is washed once with anaqueous solution of sodium bicarbonate and taken to dryness. The residueis chromatographed on 100 ml. of silica gel with methylene chloride; 50ml. fractions are collected. The solids are combined and recrystallizedtwice from ether Skellysolve B hexanes to give 0.48 g. of5-[a-(p-methoxyphenyl)styryl1-3-methylisoxazole as a mixture of isomers.melting point 6875 C.

Anal.

Calcd. for C H No,: C. 78.33; H. 5.88.

Found: c. 78.34; H. 5.55.

Using the procedure of example 1, but replacing p-methoxy phenyl3-methyl-5-isoxazolyl ketone by o-methoxyphenyl 3- methyl-S-isoxazolylketone and m-methoxyphenyl 3-methyl-5- isoxazolyl ketone is productiveof 5-[a-(o-methoxyphenyl)styryl]-3-methyl isoxazole and5-[a-(m-methoxyphenyl)styryl1-3-methyl-isoxazole, respectively.

EXAMPLE 2 S-[a-(p-METHOXYPHENYL)STYRYL1-3-METHYLISOX- AZOLE (lSOMER A)To an ice-cooled suspension of 10.8 g. of finely groundtriphenylbenzylphosphonium bromide in 100 ml. of tetrahydrofuran isadded 15.6 ml. of a l.6N solution of butyl lithium in pentane and then asolution of 5.0 g. of p-methoxyphenyl 3- methyl-S-isoxazolyl ketone(Preparation A) in l ml. of tetrahydrofuran. The resulting mixture isstirred for 1 hour in the cold and 3 hours at reflux and then treatedwith 100 ml. of saturated aqueous ammonium chloride solution. Theorganic layer is separated, washed successively with water and saturatedaqueous sodium chloride solution and then taken to dryness. The residueis chromatographed on 1 l. of Florisil with 5 percent acetone 95 percentSkellysolve B hexanes (by volume); 400 ml. fractions are collected. Thecrystalline fractions are combined and recrystallized twice frommethanol to give 3.38 g. of an isomer of5-[a-(p-methoxyphenyl)styryl]-3-methylisoxazole, melting point 110 -l 13C.

Anul. Culcd. for C H NO C. 78.33; H, 5.88.

found: C. 78.52; H. 5.90.

Using the procedure of example 2. but replacing p-methoxyphenyl3-methyl-5-isoxazolyl ketone by o-methoxyphenyl 3- methyl-5-isoxazolylketone and m-methoxyphenyl 3-methyl-5- isoxazolyl ketone is productiveof 5-[a-(o-methoxyphenyl)- styryll-3-methyl isoxazole and5-[a-(m-methoxyphenyl)styryl]-3-methylisoxazole, respectively.

EXAMPLE 3 C18 AND TRANS lSOMERS 0F S-[a-(p-METHOXYPHEN- YL)-p-METHYESTYRYLl-3-METHYLlSOXAZOLE A. MIXTURE ofcis and trans isomers ofS-[a-(p-methoxyphenyl)-p-methylstyryl]-3-methylisoxazole To anice-cooled suspension of 4.66 g. of triphenyl-pmethylbenzylphosphoniumchloride in 50 ml. of tetrahydrofuran is added 7.3 ml. of l.6N solutionof butyl lithium in pentane and then a solution of 2.5 g. ofp-methoxyphenyl 3- methyl-S-isoxazolyl ketone (Preparation A) in 50 ml.of tetrahydrofuran. The resulting mixture is stirred for l hour in thecold and 3 hours at reflux and then treated with 50 ml. of saturatedaqueous ammonium chloride solution. The organic layer is separated.washed successively with water and saturated aqueous sodium chloridesolution and then taken to dryness to yield a physical mixture of thecis and trans isomers ofS-[a-(p-methoxyphenyl)-p-methylstyryl]-3-methylisoxazole as a residue.The residue is chromatographed on 500 ml. of Florisil with 5 percentacetone percent Skellysolve B (by volume); 400 ml. fractions arecollected.

B. lsomerA The material eluted in fraction 4 is recrystallized fromSkellysolve B hexanes to give 1.65 g. of lsomer A ofS-[a-(pmethoxyphenyl)-p-methylstyryll-3-methylisoxazole, melting point 113-l 15 C.

Anal.

Found: C. 78.06; H. 6.l9.

C. lsomer B The material eluted in fractions 5 to 8 is recrystallizedfrom methanol to give 0.44 g. of lsomer B ofS-[a-(p-methoxyphenyl)-p-methylstyryl]-3-methylisoxazole, melting point146- 1 48 C.

Anal.

Calcd. for C H NO,: C. 78.66; H, 6.27.

Found: C. 78.54; H. 6.26.

Using the procedure of example 3. but replacingtriphenylp-methybenzylphosphonium chloride by the appropriatelysubstituted triphenyl-alkylbenzylphosphonium chloride and/orp-methoxyphenyl 3-methyl-5-isoxazolyl ketone by the appropriatelysubstituted alkoxyphenyl 3-methyl-5-isoxazolyl ketone is productive ofthe isomers of the corresponding S-[a-(alkoxyphenyl)-alkylstyryl]-3-methylisoxazole. Representative of theS-[a-(alkoxyphenyl)alkylstyryll-B-methyl isoxazoles so obtained are5-[a-(o-methoxyphenyl)-p-methyly y l-5-[a-(m-methoxyphenyl)-p-methylstyryl]-S-[a-(p-ethoxyphenyl)-p-methylstyryl]-5-[a-(p-propoxyphenyl)-p-methylstyryl]- -la-(pyp y rpy y y 1-5-[a-(p-isopropoxyphenyl)-o-propylstyryl]- and5-[a-(pmethoxyphenyl)-m-ethylstyryl ]-3-methylisoxazole.

EXAMPLE 4 S-[a-(p-METHOXYPHENYL)-p-CHLOROSTYRYL]-3- METHYL-ISOXAZOLE Toan ice-cold suspension of 4.90 g. of triphenyl-pchlorobenzylphosphoniumchloride in 50 ml. of tetrahydrofuran is added 7.3 ml. of l.6N butyllithium in pentane and then a solution of 2.5 g. of p-methoxyphenyl3-methyl-5-isoxazolyl ketone (Preparation A) in 50 ml. oftetrahydrofuran. The resulting mixture is stirred for 1 hour in the coldand 3 hours at reflux and then treated with 50 ml. of saturated aqueousammonium chloride solution. The organic layer is separated, washedsuccessively with water and saturated aqueous sodium chloride solutionand then taken to dryness. The residue is chromatographed on 400 ml. ofFlorisil with 2 percent acetone 98 percent Skellysolve B hexanes (byvolume); 400 ml. fractions are collected. The material eluted infractions 4-7 contains 1.51 g. of crude product. This product isrecrystallized from methanol to give 1.05 g. ofS-[a-(pmethoxyphenyl)-p-chlorostyryl]-3-methylisoxazole, melting point144.5-147 C.

Anal.

Calcd. for C,,H ClNO,: C. 70.04; H, 4.95.

Found: C. 69.90; H, 4.80.

Using the procedure of Example 4 but replacing triphenylp-chlorobenzylphosphonium chloride by the appropriately substitutedtriphenyl-halobenzylphosphonium chloride and/or p-methoxyphenyl3-methyl-5-isoxazo1yl ketone by the appropriately substitutedalkoxyphenyl 3-methyl-5-isoxazolyl ketone is productive of thecorresponding S-[a-(p-methoxyphenyl)halostyryl]-3-methylisoxazole.Representative of the EXAMPLE 5-[a-(p-METHOXYPHENYL)-m-METHOXYSTYRYL1-3-METHYL-ISOXAZOLE To an ice-cold suspension of 4.85 g.of triphenyl-m-methoxybenzylphosphonium chloride in 50 ml. oftetrahydrofuran is added 7.3 ml. of 1.6N butyl lithium in pentane andthen a solution of 2.5 g. of p-methoxyphenyl 3-methyl-5-isoxazolylketone (Preparation A) in 50 ml. of tetrahydrofuran. The resultingmixture is stirred for 1 hour in the cold and 3 hours at reflux and thentreated with 50 ml. of saturated aqueous ammonium chloride solution. Theorganic layer is separated, washed successively with water and saturatedaqueous sodium chloride solution and then taken to dryness. The residueis chromatographed on 500 ml. of Florisil with 4 1. each of 2 percentacetone 98 percent Skellysolve B hexanes (by volume) and then 5 percentacetone 95 percent Skellysolve B hexanes (by volume); 400 ml. fractionsare collected. Fractions 7 to 1 l are combined and recrystallized twicefrom Skellysolve B hexanes to give 1.26 g. of 5-[a-(p-methoxyphenyl)-m-methoxystyrylJ-J-methylisoxazole, melting point7072 C.

Anal.

Calcd. for C, H ,NO,: C. 74.74; H. 5.96.

Found: C, 74.I9; H. 5.83.

Using the procedure of example 5, but replacingtriphenylm-methoxybenzylphosphonium chloride by the appropriatelysubstituted triphenyl-alkoxybenzy1phosphonium chloride and/orp-methoxyphenyl 3-methyl-5-isoxazolyl ketone by the appropriatelysubstituted alkoxyphenyl 3-methyl-5-isoxazolyl ketone is productive ofthe corresponding S-[a-(alkoxyphenyl)alkoxystyryl]-3-methylisoxazole.Representative of the 5-[a-(alkoxyphenyl)-alkoxystyryll-3-methylisoxazoles so ob-, tained are:

5-[a-(p-methoxyphenyl)-o-methoxystyryl]- 5- la-(o-methoxyphenyl)-m-methoxystyryl 5-[a-(p-ethoxyphenyl)-p-methoxystyryl]-S-[a-(p-propoxyphenyl)-p-ethoxystyryl]-5-[a-(o-methoxyphenyl)-p-propoxystyryl]- S-[adm-methoxyphenyl)p-methoxystyrylland 5-[a-(m-isopropoxyphenyl)-p-methoxystyryl]methylisoxazole.

EXAMPLE 6 5-[a-(p-ACETOXYPHENYL)STYRYL]-3-METHYL1SOX- AZOLE To anice-cold suspension of 15.0 g. of triphenylbenzylphosphonium bromide in250 ml. of tetrahydrofuran is added 22 ml. of 1.6N butyl lithium inpentane and then a solution of 8.40 g. of pacetoxyphenyl3-methyl-5-isoxazolyl ketone (Preparation C) in 210 ml. oftetrahydrofuran. The resulting mixture is stirred for 1 hour in the coldand 3 hours at reflux and then treated with 50 ml. of saturated aqueousammonium chloride solution. The organic layer is separated, washedsuccessively with water and saturated aqueous sodium chloride solutionand then taken to dryness. The residue is chromatographed on 1.2 l. ofFlorisil with 10 percent acetone 90 percent Skellysolve B hexanes (byvolume); 400 ml. fractions are collected. Fractions 7-16 are combinedand recrystallized from acetone Skellysolve B hexanes to give 7.50 g. ofcrude product. This product is recrystallized from acetone Skellysolve Bhexanes to yield 4.2 g. of S-[a-(p-acetoxyphenyU-styryl]-3-methylisoxazole, melting point l34l 36 C.

Anal.

Calcd. for C H,,NO,: C. 75.22; H. 5.37.

Found: c. 74.87;H, 5.37

Using the procedure of example 6, but replacingtriphenylbenzylphosphonium bromide by the appropriately substitutedtriphenylvenzylphosphonium bromide and/or p-acetoxyphenyl3-methyl-5-isoxazolyl ketone by the appropriately substitutedalkanoyloxyphenyl 3 -methyl-5-isoxazolyl ketone is productive of thecorresponding S-[a-(alkanoyloxyphenyl)styryll-3-methyl-isoxazole.Representative of theS-[a-(alkanoyloxyphenyl)-styryl]-3-methylisoxazoles so obtained are:

5-[a-(o-acetoxyphenyDstyryl]- 5-[a-(m-acetoxyphenyl)styryl]-5-[a(p-acetoxyphenyl)-p-methylstyryl]5-[a-(p-acetoxyphenyl)-p-methoxystyryl]-5-[a-(p-acetoxyphenyl)-o-chlorostyryl]-5-[a-(p-propionyloxyphenyl)styryl)- 5-[a-( p-formyloxyphenyl)styryl andS-[a-(p-acetoxyphenyl)-o-methylstyryl]-3-methylisoxazole.

EXAMPLE 7 5-[a-(p-HYDROXYPHENYL)STYRYL -3-METHYLISOX- AZOLE A mixture of7.50 G. OF %-[a-(p-acetoxyphenyl)styryl]-3- methylisoxazole (example 6)and 20 ml. of 1N sodium hydroxide in ml. of methanol is heated at refluxfor 2 hours. The bulk of the solvent is removed in vacuo. The residue issuspended in water, acidified with 2.5N hydrochloric acid and extractedwith methylene chloride and either. The extracts are combined, washedsuccessively with water and saturated aqueous sodium chloride solutionand taken to dryness. The residue is recrystallized twice from aqueousmethanol to give 5.67 g. of crude product. This product isrecrystallized twice from aqueous methanol to giveS-[a-(p-hydroxyphenyl)styryl -3-methyl-isoxazole, melting point 154-60C.

Anal.

Calcd. for C ,H ,NO,: C, 77.96; H. 5.45.

Found: C, 78.26; H, 5.41.

Using the procedure of example 7, but replacing5-[a-(pacetoxyphenyl)styryl -3-methylisoxazole by the appropriatelysubstituted S-[a-(alkanoylphenyl)styryl1-3-methyl-isoxazole isproductive of the corresponding S-[a-(hydroxy-phenyl)styryl-3-methylisoxazole. Representative of the S-[a-(hydroxyphenyl)styryl]3-methylisoxazoles so obtained are:5-[a-(o-hydroxyphenyl)styryl]-3-methylisoxazole 5-[a-( m-hydroxyphenyl)styryl ]-3-methylisoxazole 5-[a-( p-hydroxyphenyl )-p-methylstyryl]-3-methylisoxazole S-[a-(p-hydroxyphenyl)-p-chlorostyryl]-3-methylisoxazole5-[a-(o-hydroxyphenyl)-o-ethylstyryl]-3-methylisoxazole and5-[a-(m-hydroxyphenyl)-o-propylstyryl]-3-methylisoxazote.

EXAMPLE 8 3-METHYL-5-[mp-a2-( I-PYRROLVIDIVNYUETHOXY]PHENYLl-STYRYLllSOXAZOLE HYDROCHLORIDE THEREOF To a solution of 2.77 g.of S-[a-(p-hydroxyphenyl)styryl]-3- methylisoxazole example 7 in 25 ml.of dimethyl formamide and 75 ml, of benzene is added 0.43 g. of 56percent dispersion of sodium hydride i mineral oil. At the end of 30minutes there is added 2.70 g. of lmixture (by weight) of toluene andl-(2-chloroethyl)pyrrolidine. Following 16 hours heating under refluxthe mixture is treated with water. The organic layer is separated,washed with water, a saturated aqueous solution of sodium chloride andtaken to dryness to give 3- methyl-S-[a- [p-[Z-(l-pyrrolidinyl)ethoxy]phenyl]styryl ]isoxazole as a gum. This gum istaken up in ether and treated with ethereal hydrogen chloride. Theprecipitated solid is separated from the mixture and recrystallizedtwice from methylene chloride-ethyl acetate to give 2.22 g. of3-methyl-5- [a-[p-[ 2-( l-pyn'olidiny) ethoxy]-phenyl ]styryl lisoxazolehydrochloride.

AND

Anal.

Calcd. for C,,H,,,N,O,- HCI Found:

C, 70.; H, 6.6L C. 69.46; H, 6.48.

EXAMPLE 9 -(a-PHENYLSTYRYL)-3-METHYLISOXAZOLE To an ice-cooledsuspension of 10.8 g. of finely ground triphenylbenzylphosphoniumbromide in 100 ml. of tetrahydrofuran is added 15.6 ml. of a 1.6Nsolution of butyl lithium in pentane and then a solution of 4.3 g. ofphenyl 3- methyl-S-isoxazolyl ketone in 100 ml. of tetrahydrofuran. Theresulting mixture is stirred for 1 hour in the cold and 3 hours atreflux and then treated with 100 ml. of saturated aqueous ammoniumchloride solution. The organic layer is separated, washed successivelywith water and saturated aqueous sodium chloride solution and then takento dryness. The residue is chromatographed on 1 l. of Florisil with 5percent acetone 95 percent Skellysolve B hexanes (by volume); 400 ml.fractions are collected. The crystalline fractions are combined andrecrystallized twice from methanol to give 5-(a-phenylstyryl)-3-methylisoxazole.

Following the procedure of example 9, but replacing phenyl3-methyl-5-isoxazolyl ketone by p-methylphenyl 3-methyl-5- isoxazolylketone is productive of S-[a-(p-methylphenyl)styryll-3-methylisoxazole.

l. A compound selected from the class consisting of a. Compounds havingthe formula wherein R is selected from the group consisting of hydrogen,alkyl of from one to three carbon atoms, inclusive, hydroxy, alkoxy offrom one to three carbon atoms, inclusive, alkanoyloxy of from one tothree carbon atoms, inclusive, and the group wherein R, and Rindividually are similar or different alkyl groups of from one to threecarbon atoms, inclusive, and when taken together with the attachednitrogen atom form pyrrolidino, loweralkylpyrrolidino, piperazino,loweralkylpiperazino, piperidino, loweralkylpiperidino, morpholine,hexamethyleneimino and homopiperazino n is an integer from 2 to 4,inclusive; and R, is selected from the group consisting of hydrogen,alkyl of from one to three carbon atoms, inclusive, alkoxy of from oneto three carbon atoms, inclusive, and halo;

b. the addition salts with pharmacologically acceptable acids of thosecompounds of the above formula wherein R contains a tertiary-aminogroup; and

c. the quaternary ammonium salts of those compounds of the above formulawherein R contains a tertiary-amino group.

2. A compound of claim 1 having the formula of I wherein R is p-methoxyand R, is hydrogen.

3. The isomer of a compound of claim 2 having the formula of I wherein Ris p-methoxy and R, is p-methyl and having a melting point of l l3l 15C.

4. The isomer of a compound of claim 1 having the formula of I wherein Ris p-methoxy and R, is p-methyl and having a melting point of l l3 "l l5C.

5. The isomer of a compound of claim 1 having the formula of I wherein Ris p-methoxy and R, is p-methyl and having a melting point of 146-l48C.

6. A compound of claim 1 having the formula 1 wherein R is p-methoxy andR, is p-chloro.

7. A compound of claim 1 having the formula l wherein R is p-methoxy andR, is m-methoxy.

8. A compound of claim 1 having the formula I wherein R is p-acetoxy andR, is hydrogen.

9. A compound of claim 1 having the formula I wherein R is p-hydroxy andR, is hydrogen.

10. A compound of claim 1 having the formula l wherein R is p-[2-(l-pyrrolidinyl)ethoxy] and R, is hydrogen.

11. The hydrochloride of the compound of claim 10.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 79Dated NOV 3 97 Inventor(s) nl Lednicer It is certified that errorappears in the above-identified patent and that said Letters Patent arehereby corrected as shown below:

Column 1 l i ne 49, for "Methy lpi pe raz l ne" read Methylpi pe raz Ino Co lumn 3, l i ne 28, for 'H" read N Column 4 l ne 1}, for 1b read Il b Column 4 l i ne 16, for "ei the r" read ethe r Column 4, l ine 30,For "-tolue nesu lfon ic" read p-to luenesu l fonic Column 4, l ine 44,for "2-pheny lprop l read 2-pheny lpropyl Column 4, l i ne #6, for"arysulfonic" read arylsulfonic Column 4, line #6, for and l i ke acidsread acids such as benzenesu l fonic,

p-toluenesu lfonic, xy lenesulfonic, and l i ke acids Column 5, l ine17, for 18 pread -[p-[ Column 5, l ine 18,

For "ethoxy l read ethoxy Column 5, l l'ne 45, for "51- I soxazo ly lread 5- soxazolyl Column 6, l ine 34, for "Methy l5" read Methy l -5-Column 8, l i ne 7, for "Methy lesty ry l re'ad Methy lstyry l Column 9,l ine 20, For "methoxypheny l -p-" read methoxypheny l )-p- Column 10, line 23, for "t ri pheny lve nzy lphosphonium" read tri pheny lbenzy lphosphonium Column 10, line 34, for U" read 1 Co lumn 10, l ine 35, Forread Column 10, l i ne 39, f0 read 1 Column 10, l i ne ll, for read 5-Column 10, l lne 52, for read l Column 10, l i ne 59, for read l Co lumn10, l i me 62, for read )RM PO-IOSO (10-69) USCOMM-DC 60376-969 U 5,GOVERNMENT PRINTING OFFICE I969 0-356-384 UNITED STATES PATENT OFFICE Pa98 2 CERTIFICATE OF CORRECTION Patent No. 3, 79 Dated November 30, 1971Inventor(s) Daniel Lednicer It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 10, line 66, for read 5-[-(p-hydroxyphenyllmethoxystyryl]-5-methylisoxazole Column 10, line 72,for

methylisoxazote" read methylisoxazole Column 10, line 75, for p- 2-(1"read -[p[2-(l Column 11, line 4, for "Example 7" read (Example 7) Column11, line 6, for 'hydride i mineral" read hydride in mineral Column 11,

line 7, for "of 1 mixture" read of a 1:1 mixture Column 11, line 29, for"hydrochlorides so obtained are: read thereof.

Representative of the 3-methyl-5-[ -[[2-(tertiaryamino)alkoxy]-phenyl]styryl]is0xazoles and hydrochlorides so obtained are: Column 11,line 30, for "[-(l-pyrrolidinyl]ethoxy]" read[2-(l-pyrrolidinyl]ethoxy]- Column 11, line 36, For v l-' read h xyl-Column 11, line 41, for "2" read 3 Column 12, line 44, for "is p-methyl"read R is hydrogen. Column 12, line 45, for "115-115 C." read 110-113 C.

Signed and sealed this 6th day of June 1972.

(SEAL) fittest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents )RM po'loso USCOMM-DC B0375-P69 U 5, GQVERNMENT PRlNTINGOFFICE? I959 0-365-33

2. A compound of claim 1 having the formula of I wherein R is p-methoxyand R1 is hydrogen.
 3. The isomer of a compound of claim 2 having theformula of I wherein R is p-methoxy and R1 is hydrogen and having amelting point of 110*-113* C.
 4. The isomer of a compound of claim 1having the formula of I wherein R is p-methoxy and R1 is p-methyl andhaving a melting point of 113*-115*C.
 5. The isomer of a compound ofclaim 1 having the formula of I wherein R is p-methoxy and R1 isp-methyl and having a melting point of 146*-148*C.
 6. A comPound ofclaim 1 having the formula I wherein R is p-methoxy and R1 is p-chloro.7. A compound of claim 1 having the formula I wherein R is p-methoxy andR1 is m-methoxy.
 8. A compound of claim 1 having the formula I wherein Ris p-acetoxy and R1 is hydrogen.
 9. A compound of claim 1 having theformula I wherein R is p-hydroxy and R1 is hydrogen.
 10. A compound ofclaim 1 having the formula I wherein R is p-(2-(1-pyrrolidinyl)ethoxy)and R1 is hydrogen.
 11. The hydrochloride of the compound of claim 10.